Cardiac amyloidosis: the need for early diagnosis

Patients with cardiac amyloidosis develop diastolic dysfunction leading to HFpEF complaining of fatigue, shortness of breath and oedema [2, 8, 18]. Syncope on exertion may occur due to the ‘fixed’ and relatively low stroke volume next to conduction disorders (bundle branch block and/or atrioventricular block) after infiltration of the conduction system. Depositions in the small (coronary) vessels, may lead to angina and jaw or leg claudication. Atrial dysfunction and atrial fibrillation due to atrial amyloid depositions may cause thromboembolism requiring antithrombotic therapy. Heart failure symptoms, left ventricular hypertrophy on imaging and signs and symptoms of other organ involvement offer an important clue, as summarised in Tab. 2.

AL amyloidosis is a primary haematological multi-organ disease, although heart and kidneys (70–80%) are predominately affected, presenting at the age of 55–60 [7, 8, 19]. Especially renal involvement leading to nephrotic syndrome may be the first manifestation next to peripheral neuropathy, autonomous dysfunction and gastro-intestinal complaints (Tab. 1; [1, 2]). Periorbital bruising and macroglossia are considered pathognomic but relatively rare. An important clue for cardiologists is severe hypotension after initiation of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blocker (ARB) therapy or clinical deterioration after introduction of β‑blockade. Isolated cardiac amyloidosis is found in approximately 5%. Carpal tunnel syndrome is less common then in ATTR amyloidosis. Multiple myeloma can be identified in 10–15%, but most patients have <20% plasma cells with bone marrow biopsy. Severe cardiac involvement at diagnosis often prevents patients from getting optimal therapy leading to a median survival of 6–12 months, which is worse than in ATTR-CA and probably caused by direct cardiotoxic effects of light chains [6, 20]. Moderate or little cardiac involvement has a much better outcome.

In ATTRwt amyloidosis, the misfolding of TTR is associated with age (formerly called senile systemic amyloidosis, SSA), mainly affecting the heart, although it has a systemic distribution [21]. Depositions in other organs are generally well tolerated, mean age at presentation is >70 years predominantly in males complaining of heart failure or atrial arrhythmias and conduction disorders. Asymmetrical left ventricular hypertrophy and ejection fraction <50% do occur and women are affected in 20% of cases [22]. As shown in Tab. 2, carpal tunnel syndrome is an important clue [1, 18]. Median survival is about 5 years from diagnosis. In ATTRm amyloidosis, the rate of cardiac versus neurological involvement depends on the underlying TTR mutation of which over 100 have been identified [23]. The most common mutations are the valine-to-isoleucine mutation at position 122 (Val122I), carried by 3–4% of the African-Americans leading to late-onset cardiac amyloidosis and the Val30Met mutation with a high prevalence in northern Portugal and Sweden [24]. The Thr60Ala (Ireland), Leu111Met (Denmark) and Ile68Leu (Italy) mutations have a more malignant course with onset at the age of 40 [5, 21]. The clinical presentation is comparable to ATTRwt amyloidosis with the addition of peripheral or autonomic nervous system involvement (Tab. 2); overall survival is estimated at 5–8 years [23].

The typical ECG in cardiac amyloidosis is characterised by low QRS voltage due to amyloid infiltration, seen in approximately 50–60% in AL-CA but in only 20% in ATTR-CA [6, 8]. Therefore, an important clue is a discrepancy between the left ventricular wall thickness and QRS voltage (red flag, Tab. 2). In approximately 50–70% of patients pseudo-infarct patterns are present, eventually leading to unnecessary coronary angiography (red flag, Tab. 2; [22]). The P wave may reflect prolonged atrial conduction or atrial dilatation. Conduction disorders occur frequently, the presence of atrioventricular block in patients with left ventricular hypertrophy should raise suspicion.

Echocardiographic findings in cardiac amyloidosis are a classic example of an infiltrative cardiomyopathy. Increased echogenicity (i.e. granular or ‘speckled’ myocardium) had good sensitivity and specificity using fundamental imaging before harmonic imaging was introduced and is not reliable anymore [5, 25]. Major findings are increased left ventricular wall thickness (>12 mm, either symmetrical or asymmetrical) in combination with the right ventricular free wall, thickened valves and pericardial effusion (Fig. 2). Global longitudinal left ventricular strain analysis may reveal a pattern of prognostically important apical ‘sparing’, but the specificity for cardiac amyloidosis needs further study. Left ventricular ejection fraction (LVEF) is mostly preserved (red flag, Tab. 2; [25]). Reduced tissue Doppler velocities of the mitral annulus are common, diastolic dysfunction is frequently present including a restrictive physiology: high E/A ratio, even absence of the A wave, shortened deceleration time, high E/e’ and severely increased atrial volumes. Importantly, atrial dysfunction can also be demonstrated by an abnormal left atrial strain and may lead to the formation of thrombi even in the absence of atrial fibrillation (atrial standstill) [26].

The advantage of CMR, besides a higher resolution, is the possibility to further characterise the myocardium using late gadolinium enhancement (LGE) imaging and T1 mapping, a quantitative technique able to detect diffuse myocardial abnormalities including amyloid burden [27]. Transmural or subendocardial LGE not fitting a coronary artery territory or including the right ventricle may be the first clue, next to suboptimal nulling due to altered gadolinium kinetics (Fig. 3). Native T1 mapping (before contrast) is typically prolonged. Postcontrast T1 mapping is decreased as the myocardial tissue reaches the null crossing at an earlier or similar inversion time as the blood pool, subsequently resulting in an increased extracellular volume (ECV) generally >40% (red flag, Tab. 2). In both ATTR-CA and AL-CA, T2 values indicative of myocardial oedema are increased and T2 is a predictor of prognosis in AL-CA [28]. CMR, similar to echocardiography, cannot differentiate between amyloidosis types.

Phosphate-based technetium tracers (⁹⁹mTc-PYP, ⁹⁹mTc-MDP, ⁹⁹mTc-DPD), normally used for bone scintigraphy, accumulate in the presence of ATTR-CA although the exact mechanism is unclear. Uptake in AL-CA, Fabry disease and hypertrophic cardiomyopathy is absent or low [17]. Visual grading is based on the work by Perugini ranging from grade 0 (no uptake) to grade 3 if cardiac uptake is higher than in bone [29]. Grade 2 and 3 uptake in the absence of a monoclonal protein showed a 100% specificity and positive predictive value for ATTR-CA without the need for additional histology [30]. Importantly, in all other cases (i.e. low-grade uptake, positive light chains) cardiac and/or tissue biopsy is necessary to rule out AL-CA and more rare forms of amyloidosis (AA, AApoA1) [3]. Although positive emission tomography (PET) using ¹⁸F-Florbetapir and ¹¹C-PiB to image β‑amyloid looks promising, it is not routinely used yet [31, 32].

In case of ongoing clinical suspicion, nuclear imaging with low-grade or high-grade tracer uptake in combination with positive monoclonal protein, EMB is necessary to correctly type the underlying amyloidosis (Fig. 4). EMB should be performed by experienced clinicians and trained pathologists. Congo red will demonstrate amyloid depositions as red staining under bright light and shows apple-green birefringences under polarised light, which should be followed by immunohistochemistry. Mass spectrometry after laser dissection is increasingly being used to determine the specific amyloid type especially when there is also some degree of monoclonal gammopathy [3, 7].

Standard laboratory screening may reveal kidney and liver involvement. Serum/urine immunofixation in combination with a serum-free light chain assay will evaluate light chain abnormalities [1, 8]. In chronic kidney disease impaired renal filtration leads to altered κ/λ ratios [5]. N‑terminal prohormone brain natriuretic peptide (NT-proBNP) levels are often elevated to a disproportionally high levels due to toxicity of the precursor proteins (red flag, Tab. 2). Troponins are chronically elevated without rise/fall. Both troponin and NT-proBNP have prognostic implications in AL-CA and in ATTR-CA [20, 33]. Importantly, diagnosing AL-CA based on plasma dyscrasias and a positive tissue biopsy alone can be insufficient since 20% of patients with ATTR-CA also have a non-related clonal immunoglobulin abnormality [7]. When AL amyloidosis is suspected, final diagnosis is established in close collaboration with the haematologists for which a bone marrow biopsy is essential to confirm plasma cell dyscrasia. If a fat biopsy is performed, a negative result does not rule out amyloidosis because of lower sensitivity [23]. In case of ATTR-CA, TTR gene sequencing is recommended to confirm or exclude ATTRm, as well as other forms of hypertrophic cardiomyopathy, if indicated.

Pharmacological management in cardiac amyloidosis is different from the general management of heart failure as commonly used medication can have important negative consequences (Tab. 3). Diuretics are the cornerstone in symptom management often combined with mineralocorticoid receptor antagonists. This is more challenging in AL-CA with multiple organs affected, giving an increased risk for renal failure or orthostatic hypotension. To avoid underfilling, sodium and fluid restriction are important to keep patients euvolemic with the smallest amount of diuretics possible [8]. Midodrine is sometimes used to treat orthostatic hypotension, ACE inhibitors and ARB are poorly tolerated especially in AL-CA [7]. The use of β‑blockers should generally be avoided; an increased heart rate is the only way to maintain adequate cardiac output in advanced disease. Non-dihydropyridine calcium channel blockers (i.e. verapamil, diltiazem) and digoxin are contra-indicated as toxicity may occur quickly due to abnormal binding to amyloid fibrils [36, 37]. In case of supraventricular arrhythmias, amiodarone should be considered next to catheter ablation. Importantly, anticoagulation should be considered even in patients with sinus rhythm or low CHA₂DS₂VASC score (congestive heart failure, hypertension, age ≥75 years [doubled], diabetes mellitus, prior stroke [doubled]-vascular disease, age 65–74, sex category) given the high incidence of atrial thrombi (atrial standstill), although randomised trials are lacking [26]. Careful monitoring for thrombocytopenia is necessary after chemotherapy in AL-CA. Ventricular arrhythmias do occur, but implantable cardioverter defibrillator (ICD) therapy is usually not indicated as sudden cardiac death (SCD) is mostly caused by bradycardia or adequate rhythm with pulseless electrical activity [38, 39]. According to the general guidelines for bradypacing, implantation of a pacemaker should be considered, but it remains unclear whether this prevents SCD. QT-prolonging medication should be given under careful monitoring, as especially anti-emetics or QT-prolonging prophylactic antibiotics necessary during chemotherapy can be challenging. Finally, only in highly selected patients a heart transplantation may be considered in isolated AL-CA in combination with chemotherapy and stem cell transplantation. Widespread experience is lacking and this has not been performed in the Netherlands [40].

Patients must be referred to the haematologist to initiate chemotherapy targeting the clonal plasma cells [7, 34]. Treatment-related mortality is high as the treatment by itself can be cardiotoxic leading to worsening heart failure. Although chemotherapy followed by autologous stem cell transplantation (SCT) is the preferred therapy to obtain complete remission, only a minority of patients are eligible after patient selection [7, 8, 41]. Severe cardiac involvement is an important contraindication (serum NTproBNP level is >5000 pg/ml, serum troponin T level is >0.06 ng/ml, LVEF <45%, New York Heart Association [NYHA] class ≥ III) next to severe kidney dysfunction, hypotension, age >70 years and impaired performance status [34, 35].

Although classically seen as a lethal disease without specific treatment, several disease-modifying drugs have been developed recently interfering at different points in the TTR amyloidogenesis pathway [5]. Gene silencers interfere with TTR protein synthesis in the liver including patisiran, a small interfering ribonucleicacid (siRNA) in a lipid nanoparticle targeting hepatocytes. Patisiran reduced TTR protein levels in ATTRm patients with neuropathy slowing disease progression (Apollo phase III trial) and led to a reduction in hospitalisation and/or all-cause mortality in the ATTR-CA[10]. Inotersen, an antisense oligonucleotide, showed substantial benefit in ATTRm patients with polyneuropathy but safety concerns were raised as thrombocytopenia and glomerulonephritis were reported [42]. Next to gene silencing, stabilisers preventing TTR dissociation have been investigated. Diflunisal, an old non-steroidal anti-inflammatory drug (NSAID) stabilising the TTR tetramer in patients with ATTRm and polyneuropathy showed a reduction in the rate of progression [43]. It was reasonably tolerated in a small open-labelled study, but larger trials assessing common NSAID side effects (gastro-intestinal bleeding, kidney dysfunction, worsening heart failure) are necessary [44]. Recently, a multicentre placebo-controlled phase III study showed a reduction of all-cause mortality and hospitalisations in both ATTRm and ATTRwt patients treated with the oral TTR stabiliser tafamidis [9]. Other potential options are Green Tea extract, capable of stabilising the TTR protein, and doxycycline combined with biliary acid, lowering TTR depositions. However, these compounds have only been studied in small animal models and an open label study with 20 patients [45]. Liver transplantation in ATTRm is an option in selected cases without cardiac involvement, but timing of this major operation is difficult and follow-up showed an accelerated occurrence of wild-type ATTR after transplantation with extensive cardiac depositions [11].

Several trials are underway investigating the application of antibodies recognising amyloid fibrils to induce phagocytosis including an anti-amyloid antibody 11-1F4 (phase I, NCT02245867) and serum amyloid P (SAP) antibody (phase I, NCT01777243) although some safety issues remain to be investigated [5, 46]. Investigation of NEOD001 (phase III, NCT02312206), an antibody targeting circulating and deposited amyloid, was discontinued after a negative futility analysis [47]. Another option is doxycycline showing an inhibitory effect on fibrillogenesis in transgenic AL amyloidosis mice as well as in stage III AL-CA patients in a small retrospective study leading to increased survival [48]. A prospective trial investigating doxycycline is currently enrolling patients [49].